title: Anandamide produced by Ca(2+)-insensitive enzymes induces excitation in primary sensory neurons.
abstract: The endogenous lipid agent N-arachidonoylethanolamine (anandamide), among other effects, has been shown to be involved in nociceptive processing both in the central and peripheral nervous systems. Anandamide is thought to be synthesised by several enzymatic pathways both in a Ca(2+)-sensitive and Ca(2+)-insensitive manner, and rat primary sensory neurons produce anandamide. Here, we show for the first time, that cultured rat primary sensory neurons express at least four of the five known Ca(2+)-insensitive enzymes implicated in the synthesis of anandamide, and that application of 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine-N-arachidonoyl, the common substrate of the anandamide-synthesising pathways, results in anandamide production which is not changed by the removal of extracellular Ca(2+). We also show that anandamide, which has been synthesised in primary sensory neurons following the application of 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine-N-arachidonoyl induces a transient receptor potential vanilloid type 1 ion channel-mediated excitatory effect that is not inhibited by concomitant activation of the cannabinoid type 1 receptor. Finally, we show that sub-populations of transient receptor potential vanilloid type 1 ion channel-expressing primary sensory neurons also express some of the putative Ca(2+)-insensitive anandamide-synthesising enzymes. Together, these findings indicate that anandamide synthesised by primary sensory neuron via a Ca(2+)-insensitive manner has an excitatory rather than an inhibitory role in primary sensory neurons and that excitation is mediated predominantly through autocrine signalling. Regulation of the activity of the Ca(2+)-insensitive anandamide-synthesising enzymes in these neurons may be capable of regulating the activity of these cells, with potential relevance to controlling nociceptive processing.
authors.affiliation: Section of Anaesthetics, Pain Medicine and Intensive Care, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, Chelsea and Westminster Hospital, 369 Fulham Road, London, SW10 9NH, UK.
authors.forename: Angelika
authors.initials: A
authors.lastname: Varga
authors.forename: Agnes
authors.initials: A
authors.lastname: Jenes
authors.forename: Timothy H
authors.initials: TH
authors.lastname: Marczylo
authors.forename: Joao
authors.initials: J
authors.lastname: Sousa-Valente
authors.forename: Jie
authors.initials: J
authors.lastname: Chen
authors.forename: Jonothan
authors.initials: J
authors.lastname: Austin
authors.forename: Srikumaran
authors.initials: S
authors.lastname: Selvarajah
authors.forename: Fabiana
authors.initials: F
authors.lastname: Piscitelli
authors.forename: Anna P
authors.initials: AP
authors.lastname: Andreou
authors.forename: Anthony H
authors.initials: AH
authors.lastname: Taylor
authors.forename: Fiona
authors.initials: F
authors.lastname: Kyle
authors.forename: Mohammed
authors.initials: M
authors.lastname: Yaqoob
authors.forename: Sue
authors.initials: S
authors.lastname: Brain
authors.forename: John P M
authors.initials: JP
authors.lastname: White
authors.forename: Laszlo
authors.initials: L
authors.lastname: Csernoch
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Di Marzo
authors.forename: Laki
authors.initials: L
authors.lastname: Buluwela
authors.forename: Istvan
authors.initials: I
authors.lastname: Nagy
mesh_terms: D000200:Action Potentials; D000818:Animals; D001095:Arachidonic Acids / Q000096:biosynthesis / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism*; D002478:Cells, Cultured; D063388:Endocannabinoids / Q000096:biosynthesis / Q000378:metabolism*; D005727:Ganglia, Spinal / Q000166:cytology / Q000201:enzymology / Q000378:metabolism; D054500:Group IB Phospholipases A2 / Q000235:genetics / Q000378:metabolism; D008245:Lysophospholipase / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010714:Phosphatidylethanolamines / Q000737:chemistry / Q000494:pharmacology*; D010727:Phosphoric Diester Hydrolases / Q000235:genetics / Q000378:metabolism; D053284:Polyunsaturated Alkamides / Q000378:metabolism*; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22 / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011984:Sensory Receptor Cells / Q000201:enzymology / Q000378:metabolism* / Q000502:physiology; D050916:TRPV Cation Channels / Q000235:genetics / Q000378:metabolism
chemical_list: C000595362:1,2-dioleoyl-sn-glycero-3-phosphoethanolamine-N-arachidonoyl; D001095:Arachidonic Acids; D063388:Endocannabinoids; D010714:Phosphatidylethanolamines; D053284:Polyunsaturated Alkamides; D050916:TRPV Cation Channels; C493921:TRPV1 protein, mouse; D054500:Group IB Phospholipases A2; D008245:Lysophospholipase; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22; D010727:Phosphoric Diester Hydrolases; C038133:glycerophosphodiester phosphodiesterase; D002118:Calcium; C078814:anandamide